As stated in the Welcome note of this symposium “Skeletal dysplasias are rare diseases and the annual symposium is important to share medical knowledge with colleagues in different countries. We hope to attract all medical professionals who are working in – or are interested in – the field of skeletal dysplasias. This includes both caregivers, clinicians, scientist, and students“.

On the day 2 of the event, a full session will be dedicated to achondroplasia, on the following topics:

On March 22, 2018, FDA, the US Food & Drug Administration, will conduct a public advisory committee meeting on achondroplasia. The purpose of this meeting to discuss the major objectives of a phase 3 drug development program indicated for the treatment of children with achondroplasia.

FDA values patient perspective on the development of pharmaceutical treatments for achondroplasia and this meeting presents individuals with achondroplasia and their families a valuable opportunity to provide FDA with input on important topics. These topics include the types of clinical trial endpoints that would have a clinically meaningful impact on patients’ functional or psychological well-being and other considerations on the design of clinical trials involving people with achondroplasia.

The meeting’s open public session will take place on March 22, 2018, from 10:30 a.m. to 5:30 p.m. at our location in Silver Spring, MD, just outside of Washington, DC). Individuals, families, and others (patient organizations) may provide testimony in person at this meeting’s open public comment. Anyone interested in providing public comment at the meeting should register with Marieann.Brill@fda.hhs.gov by March 7.

There are a limited number of speaking slots. In addition, individuals, families, and others can submit a written commenton the topic of achondroplasia and development of potential treatments to the public docket. Additional details can be found in the federal register notice of the meeting.

FDA is seeking to collect a rich and diverse set of patient perspectives on this topic. We have developed a flyer, attached, with information relevant to this meeting and encourage you to disseminate it to any individuals or groups who may be interested in this meeting.

Preview of the information flyer. To read the flyer in full, click on the following link: AchondroplasiaAC

Therachon announced today, 14 February 2018, the beginning of Phase 1 for the clinical trial with TA-46 for achondroplasia.

This trial will take place in The Netherlands, with 70 adult healthy volunteers and it will be:

randomized – A study in which the participants are divided by chance into separate groups that compare different treatments or other interventions. Using the chance to divide people into groups means that the groups will be similar and that the effects of the treatments they receive can be compared more fairly. At the time of the trial, it is not known which treatment is best. Pubmed health

placebo-controlled – Studies of new drugs often compare the effects of an investigational drug with the effects of a placebo. The reason for using a placebo control is that the benefits of takingmedications are not always due to the drug itself. These benefits are called “placebo effects.” An example is when an investigator’s enthusiasm about a new medication sometimes influences the patient’s response. In a double-blind, placebo-controlled research design, the doctors, nurses working directly with patients, and participants themselves involved in the study, will not know which group patients are in. PsychCentral

double-blind trial – is a trial where neither the researchers or patients/participants know what they are getting (the drug or the placebo). The computer gives each patient a code number. And the code numbers are then allocated to the treatment groups. Cancer Research UK

The number of participants vary significantly, depending on the study and if teh new medicine is for a more common condition or a rare condition. Credits: Global Medical Institutes

The trial is designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of TA-46.

Luca Santarelli, Therachon´s CEO said that this is “an important milestone for the company,”.

Beyond Achondroplasia has published more information about TA-46 previously (read the first article). The company has high expectations that Ta-46 may show significant therapeutic impact in achondroplasia as may improve anatomical proportions and prevent complications related to achondroplasia, that start to occur in early life phases.

Next steps

Is important to know the timelines for this phase 1 trial, namely the duration of this trial as also the results of safety, tolerability and mechanism of the drug in these healthy volunteers and then, after positive results, know the expected dates of the beginning of phase 2, with children with achondroplasia.

How is expected TA-46 to work?

TA-46 acts as a ligand trap can reduce the superactivation of the mutated receptor FGFR3 (that is overworking in achondroplasia, which reduces the multiplication and development of chondrocytes, that the cells that give origin at the growth plate level, to the bone formation).

TA-46 is being developed as a weekly subcutaneous drug for children and adolescents living with the disease.

This is a short videos series from EMA, the European Medicines Agency, about new medicines reaching the market and also about the works of regulators, EMA and FDA, which is focused on protecting patients and to approve the best possible new medicines.

Ascendis Pharma, a company funded in 2007, applies the TransCon technology which combines a prodrug with a sustained-release technology. This way, the company can offer products with a predictable and sustained release of an unmodified parent drug.

Before heading for the publications the company released in 2017 in selected events, is important to explain some concepts.

What is a prodrug?

A prodrug is an inactive medication or compound (the same as having no action), and after being administrated, it is converted within the body (metabolized) into a pharmacologic active drug.

Prodrugs undergo an enzymatic and/or chemical transformation in vivo (inside the body) to release the active drug: the parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving several properties of active agents: physicochemical, biopharmaceutical or pharmacokinetic.1

Example of a prodrug. Credits: www.clayton.edu

During 2017 Ascendis Pharma released relevant information on the TransCon CNP. Through selected publications, the company shows high expectations on the efficacy of TransCon CNP in improving the quality of life in achondroplasia and reducing complications. In the company website it can be read the following:

Our preclinical studies of TransCon CNP have been encouraging. Continuous exposure to TransCon CNP has been found in preclinical studies to be more efficacious at inducing skeletal growth compared to once-daily injections. In preclinical safety studies, a low Cmax due to slow release of CNP has been shown to improve hemodynamic tolerability. And, the half-life extension observed confirms the potential of convenient weekly dosing in patients with achondroplasia. Additionally, preclinical data suggest a trend toward bone growth associated with TransCon CNP. Building on these positive results, Ascendis Pharma plans to submit an Investigational New Drug Application for TransCon CNP in the fourth quarter of 2017.Ascendis pharma

What is the Cmax?

Is the maximum concentration of the drug that is measured in the plasma after one dose administration. 2 The concentration of a drug is the abundance of a compound divided by the total volume of a mixture. The following image gives a simple example how to reach the concentration value of a mixture.

So, once the TransCon CNP shows a low Cmax, this avoids side effects in the body after the administration of CNP, namely the reduction of blood pressure and an increase of heart rate has shown by other CNP (as BMN-111).

And what is the plasma?

Is the clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma.3 Blood is composed of blood cells suspended in blood plasma, that can be separated by centrifugation (a process used to separate substances that as mixed together).

What is the half-life of a drug?

Is the time that takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. 4

So due to an increased half-life of the TransCon CNP, the company sees the potential of having one administration per week of the drug instead of a daily administration.

The reduction of the ossification of the areas around the foramen magnum, the synchondroses (IOSA). Credits: Ascendis Pharma

Main conclusions:

In a murine model of ACH, TransCon CNP prevented the closure of synchondroses and resulted in an improvement in foramen magnum and skull shape, suggesting normalization of the overall skull contour.

These results suggest that the early administration of TransCon CNP may alleviate the risk of foramen magnum stenosis that leads to some of the most serious clinical complications of ACH. Ascendis Pharma

BioMarin Pharmaceutical sent to patient organizations an update of the clinical development program for BMN-111. The current status of the achondroplasia clinical programme is described in the document below.
BioMarin’s investigational therapy for achondroplasia, BMN 111, is currently under investigation and has not been approved for use in any country.

Study 111-301

This trial is a phase 3 placebo-controlled trial with BMN-111, includes children from 5 to 17 years of age and approximately 110 participants globally. In this trial, participants are randomly selected to be included in the placebo group or in the drug group.

Outcomes of study 111-301

The primary outcome of the trial is to evaluate a change in the rate of growth or change in height. Secondary outcomes include measurements of health through evaluating health-related quality of life scores, other
associated symptoms, sleep quality as well as major illnesses and surgeries.

Duration

This trial lasts for 52 weeks and participants will have to have to complete a minimum of 6 months in theobservational trial (111-901) before they can be selected for the Phase 3 (111-301) trial.
Participants on placebo can receive the investigational therapy, or the BMN-111, after the 1 year trial period is
complete.

Study 111-501

BioMarin is preparing a new study, the 111-501, on the Lifetime Impact of Achondroplasia Study in Europe (LIAISE) is an observational study (so, no drug will be included) looking at the impact on quality of life, healthcare resource use, clinical, socioeconomic and psychosocial state of individuals living with achondroplasia.

This study is recruiting up to 300 participants between 5 and 70 years of age and will be opening in the following countries between now and early 2018: Germany, Spain, Italy, Sweden, and Denmark. Participation in the

study will include a 5-year review of historical clinical data as well as data obtained using questionnaires.

The International Skeletal Dysplasia Society meeting was held in Bruges between the 20th and 23rd September 2017, with the presence of world-renowned geneticists and clinicians with interest in skeletal dysplasias; also some pharmaceutical companies and patients representatives from all around the world were present.

The companies that were present and that are currently developing medicines for achondroplasia were, by alphabetic order: Ascendis Pharma, BioMarin, and Therachon.

To add some clarification on the concepts regarding the Meclozine representation by Hiroshi Kitoh, that presented “Oral administration of meclozine for the treatment of short stature in achondroplasia”

His team observed that cutting-off the FGFR3 signaling in-vitro promoted (produced) longitudinal bone growth in transgenic ACH mice (mice that were genetically changed to be born with the ACH mutation). The team has been investigating which is the optimal dose of meclozine for the treatment of short stature in ACH for further clinical application in children.

In vitro - In vitro (Latin for "within the glass") refers to the technique
of performing a given procedure in a controlled environment outside of a
living organism. Many experiments in cellular biology are conducted outside
of organisms or cells. One of the weaknesses of in vitro experiments is
that they fail to replicate the precise cellular conditions of an organism.
In mpkb.org

FGFR3 ach mouse – Mouse models are currently available for genetic
research and include thousands of unique inbred strains and genetically
engineered mutants. In Genome.gov.
FGFR3 ach mouse model is a mutant strain developed for mice to be born
with the achondroplasia mutation, to conduct scientific studies.

For this study, the team administered orally 1, 2 or 20 mg/kg/ day of meclozine to 7-day-old FGFR3 ach mice for 10 days. The body lengths were measured during the treatment periods and at the end of the treatment, the mice were subjected to micro-computed tomography (micro-CT) scans for calculating the bone length and bone volume.

The pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) of 2 mg/kg of meclozine to mice was similar to those of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. The body lengths of FGFR3 ach mice were increased by oral administration of 1 or 2 mg/kg/day of meclozine and the bone volume and trabecular bone quality were improved by meclozine treatment. Treatment of 20 mg/kg/day of meclozine, however, showed no positive effects on bone growth of mutant mice.

Pharmacokinetics: Pharmacokinetics is the study of drug absorption,
distribution, metabolism, and excretion. A fundamental concept in
pharmacokinetics is drug clearance, that is, elimination of drugs
from the body. In Principles of Pharmacokinetics

Micro-computed tomography: Enables a non-invasive inspection to
screen anatomical changes in small animals. Once the dose received
by the small animal can be a critical concern in the research, the
advantages of micro-CT include high resolution, high sensitivity
to bone and lung, short scan time and cost-effectiveness.
In Li H et al., 2008

Kitoh finished saying that they confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined. Also, the team is aiming to start a phase 1 clinical trial in Nagoya, Japan in children with ACH, between the end of 2017 and beginning of 2018. The study design is still not disclosed.

Metabolic studies on Achondroplasia

But one of the most relevant moments during ISDS was a study presented by Celine Saint-Laurent, a young researcher working in Elvire Gouze´s team in Nice, France (and in collaboration with Therachon). In her presentation, Celine showed that there is a link between the FGFR3 mutation and the metabolic complications related to achondroplasia.

Prior to this study in a mouse model with ACH, Celine firstly conducted a retrospective longitudinal study in children and adolescents with achondroplasia carrying the most frequent mutation of achondroplasia: the G380R FGFR3 mutation. Anthropometric, densitometric measures and several blood parameters were recorded from birth onward during follow up visits and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old.

Celine’s study confirmed that there are metabolic disturbances in achondroplasia patients, that are unexpectedly not associated with classical obesity complications. Indeed, the data gathered showed that while patients with achondroplasia usually develop abdominal obesity, this does not correlate with an increase of typical risk factors of obesity such as high glucose, insulin or lipid levels and that they do not appear to develop diabetes.

In the mouse model study, Celine injected the mice with Flag-soluble FGFR3 (sFGFR3) during the mice growth period and could confirm that the bone growth was restored and the metabolic deregulations were corrected with the administration of soluble FGFR3. The researchers concluded that sFGFR3 proved to be a promising treatment for achondroplasia by restoring bone growth and also by preventing the metabolic deregulations and the development of obesity.

Anthropometric measurements: are used to assess the size, shape and
composition of the human body. Some common methods used to gather
these measurements are BMI, waist-to-hip ratio, skin-fold
test and bioelectrical impedance.

It is important to mention that families interested in having their children enrolled in BioMarin ongoing observational study (111-901) and interventional clinical trial (111-301), have to contact the centers that are conducting the clinical trial driectly, listed here.

Pharmaceutical companies DO NOT recruit patients for clinical trials. The companies, such as BioMarin, select the clinical centers (hospitals) in which their trial will take place and is the trial coordinator of that clinical center (usually a chief clinician), that recruits patients and who must be contacted for recruitment.

From the 20th to the 23rd September 2017, it will take place in Bruges, Belgium, the ISDS meeting.

The ISDS is registered as a non-profit organization and the principal aim of the Society is to promote scientific progress in the field of skeletal dysplasias and dysostoses. To this aim, the society organizes meetings on a two-year basis.

The focus of the meeting will be on the clinical, radiographic and molecular aspects of rare and genetic disorders of the skeleton with special attention to the newest discoveries within this field.
Clinicians and researchers with interest in rare bone disorders will attend this meeting, as representatives from industry and patient groups.

The themes related to achondroplasia that will be presented during the course of the three days meeting will be:

Turning this title into something comprehensible, the researchers said that the 5 agents/products (SU5402, PD173074, AZD1480, AZD4547 and BGJ398), known as TKIs (Tyrosine kinase inhibitors) showed great results in blocking FGFRs tyrosine kinases in dish cells (plates where the researchers put specific cells into a culture to be tested). The image below is an example of a cell culture plate.

FGFR 3 is the receptor where the mutation of achondroplasia is in chondrocytes and knowing that TKIs can block FGFR3, they can also block the other FGFRs. This means that TKIs target not just FGFR3 but all or almost all FGFRs.

FGFR3 is a major physiological negative regulator of bone growth, and therefore a safe and effective FGFR3 inhibitor would undoubtedly revolutionize the treatment of short-stature syndromes in general, possibly including many that are unrelated to FGFR3. 3

Credits: Khan Academy

So, in 2016, the team concluded that the 5 FGFR TKIs evaluated were poor candidates for therapy for achondroplasia, mainly because TKIs exhibited significant off-target activity. What does this mean?TKIs lack specificity for FGFR3, attack the other FGFRs, and show cell toxicity which would compromise TKIs’ use for treatment of achondroplasia. 3

Although Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, and these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. This occurs because tyrosine kinases are widely distributed with specific functional roles in different organs. 2

ARQ 087 is a tyrosine kinase inhibitors that was tested in cultured chondrocytes (dish cells), and the team observed that ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation as inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. This means that in the cultured chondrocytes with the achondroplasia mutation and with ARQ 087, chondrocytes could grow and multiply as they do in a typical growth plate. Unfortunately, ARQ 087 has an off-target action too and blocks FGFR1, FGFR2 and FGFR3.

The main conclusion of the study is the following:

“The off-target effects of ATP-competitive TKIs represent a major obstacle compromising their use in the clinic, despite the fact that even serious side-effects may be tolerated in cancer, where the main objective is patient survival. In contrast, theside effects might not be acceptable in ACH or craniosynostoses, where the main treatment objectives are to increase stature height and correct disproportionate cranial development, respectively.” 4

This research proves that TKIs are not an appropriate selection to treat achondroplasia.

Developing new studies for achondroplasia can be very demanding and time-consuming, but patients trust that researchers do the best they can to deliver results that, ultimately, can be converted in a treatment and reduce the complications originated by achondroplasia: limbs and trunk disproportionality, neurologic, respiratory issues, orthopedic complications, negative social image, among others issues that are concerns and raise problems throughout life.

Not every study will originate a new medicine, but most studies will help researchers decide which way to go and which not to.

Author Comment: The title and text of this post was amended after reconsideration of previous content.